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- Title
Increased endothelial cell permeability in endoglin-deficient cells.
- Authors
Jerkic, Mirjana; Letarte, Michelle
- Abstract
Endoglin (ENG) is a TGF-β superfamily coreceptor essential for vascular endothelium integrity. ENG mutations lead to a vascular dysplasia associated with frequent hemorrhages in multiple organs, whereas ENG null mouse embryos die at midgestation with impaired heart development and leaky vasculature. ENG interacts with several proteins involved in cell adhesion, and we postulated that it regulates vascular permeability. The current study assessed the permeability of ENG homozygous null (Eng-/-), heterozygous (Eng+/-), and normal (Eng+/+) mouse embryonic endothelial cell (EC) lines. Permeability, measured by passage of fluorescent dextran through EC monolayers, was increased2.9- and 1.7-fold for Eng-/- and Eng+/- ECs, respectively, compared to control ECs and was not increased byTGF-β1 or VEGF. Prolonged starvation increased Eng-/- EC permeability by 3.7-fold with no effect on control ECs; neutrophils transmigrated faster through Eng-/- than Eng+/+ monolayers. Using a pull-down assay, we demonstrate that Ras homolog gene family (Rho)Ais constitutively active in Eng-/- and Eng+/- ECs. We show that the endothelial barrier destabilizing factor thrombospondin-1 and its receptor-like protein tyrosine phosphatase are increased, whereas stabilizing factors VEGF receptor 2, vascular endothelial-cadherin, p21-activated kinase, and Ras-related C3 botulinum toxin substrate 2 are decreased in Eng-/- cells. Our findings indicate that ENG deficiency leads to EC hyperpermeability through constitutive activation of RhoA and destabilization of endothelial barrier function.
- Subjects
TRANSFORMING growth factor-beta induced protein; VASCULAR endothelial growth factor receptors; THROMBOSPONDIN-1; ENDOTHELIAL cells; ENDOGLIN
- Publication
FASEB Journal, 2015, Vol 29, Issue 9, p3678
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.14-269258